1. Field of the Invention
The present invention relates to a computerized laser controller for photodynamic therapy ("PDT") treatment of various types of cancerous tumors, and in particular, to a system for optimizing the effect of the photodynamic therapy in treating the cancer by cycling the laser operation to ensure that the proper levels of singlet oxygen is present in the tumor. A medicated tumor is irradiated by a laser with a specific wavelength such that the cancerous tumor is destroyed with only minimal damage to the healthy tissue surrounding the tumor. Anoxia induced within the tumor is minimized to improve the therapeutic effectiveness of the PDT process.
2. Summary of Related Art
Cancer research has resulted in a number of important developments in the diagnosis and treatment of cancer. Although significant improvements have been developed for surgery, radiotherapy, chemotherapy, and related treatments, all such treatments are associated with major debilitating side effects. The side effects, such as trauma, immunosuppression, or toxicity, present further obstacles to the patient in ill-health.
One of the newer treatment methods which has been developed for intractable tumor masses is photodynamic therapy. Photodynamic therapy offers a viable, less toxic, less invasive, and less painful procedure for treatment of cancer. Solid tumors, frequently characterized by a poorly developed vascular system and sometimes inoperable, are good candidates for photodynamic therapy.
Photodynamic therapy generally involves the infusion of photoactivatable dyes, followed by appropriate long wavelength irradiation of the tumors to generate a lethal shortlived species of oxygen which destroy the neoplastic cells. Early photodynamic therapy agents were derived from natural sources or from known chemicals originating in the dye-stuffs industry.
Improved chemically pure photoactivatable dyes have been chemically synthesized for use in photodynamic therapy. The dyes used in photodynamic therapy are compounds with low intrinsic toxicity, are efficient photosensitizers for singlet oxygen production, have selective uptake in rapidly proliferating cells, are rapidly degraded and eliminated from the tissues after administration, and are available as chemically pure and stable compounds easily subject to synthetic modification.
The latest photodynamic therapy dye compounds exhibit a maximum wavelength absorption at between about 600 to 900 nm. The longer wavelength absorption characteristics facilitates the use of such compounds as photodynamic therapy agents while minimizing the competing light absorption by blood and other tissues which absorb in the shorter wavelength regions below 600 nm.
The photodynamic therapy agents are prepared in a pharmaceutical composition or preparation for either topical and parenteral applications. After administration of a therapeutically effective amount of the agent to a patient having a treatable condition, such as a solid tumor, the patient's affected body area is exposed to a sufficient amount of light having an appropriated wavelength for absorption by the particular photodynamic therapy agent used. Irradiation of the accumulated agent generates singlet oxygen which is thought to be the actual lethal species responsible for destruction of the neoplastic cell.
Photodynamic therapy agents, in general, are minimally toxic in the unexcited state. The agents can be repeatedly photoactivated and lead each time to cell-lethal events, by the generation of singlet molecular oxygen. The half-life of singlet molecular oxygen is measured in microseconds, and the target cell is affected without the opportunity for migration of the lethal singlet molecular oxygen to healthy neighboring tissue. Destruction of the target cell tissue commences promptly upon irradiation of the agent, and ceases abruptly when irradiation is stopped.
The time and duration of therapy can be selected by the physician or radiologist. The dosage of photodynamic therapy agent may be varied according to the size and location of the target tissues which are to be destroyed and the method of administration. Irradiation generally takes place not less than one hour or more than four days after parenteral administration of the agent. With topical agents, irradiation may commence as soon as 10 minutes after application.
The oxygen tension of tumors treated with ionizing radiation is an important factor influencing radiosensitivity and therapeutic response. Treatment under hyperbaric oxygen conditions and fractionation of the light dosage are two methods for exploiting the increased sensitivity of well-oxygenated tumors.
Tumor destruction in photodynamic therapy is accomplished through the formation of singlet oxygen, and the subsequent reaction of singlet oxygen with cellular substrates. Considerable attention has been given to the calculation and measurement of the sensitizing agent and the light dose delivered to a tumor undergoing photodynamic therapy. While sufficient quantities of light and photodynamic therapy agent are prerequisites for the photodynamic effect, it is clear that the production of cytotoxic levels of singlet oxygen depends directly upon the presence of ground state molecular oxygen as well.
Photodynamic therapy is dependent on the presence of molecular oxygen in the tumor tissue. Tumor response to the same light and agent dose varies significantly with the rate of light delivery to the neoplastic cell. Oxygen depletion at high dose rates may contribute to diminished tumor cell killing. Photodynamic therapy is capable of consuming oxygen at a rate that is sufficiently high to move a fraction of the treated tumor volume into very low oxygenation, thereby protecting these cells from damage mediated by singlet oxygen.
The intercapillary tissue can become hypoxic shortly after treatment begins. Anoxia induced by PDT outside a critical radius from the capillaries can serve to inhibit direct tumor cell destruction. The cells immediately surrounding the capillaries, to which oxygen may diffuse from the microvasculature, are directly affected by the PDT reaction. Fractionating the exposure to light may enhance the efficacy of the PDT treatment. Cycling the photoirradiation creates dark intervals which halt the mechanisms of the PDT reaction and allow time for oxygen to diffuse back into the anoxic intercapillary spaces, resulting in periodic production of and exposure to the toxic effects of singlet oxygen.
Photodynamic therapy has been used both experimentally and clinically for treatment of cancer tumors. Fractionating has improved the results of photodynamic therapy by overcoming oxygen depletion. However, a system to optimize the fractionation of the light dose through laser control is needed to improve the clinical applications of photodynamic therapy.
A number of researchers have discussed the concept of fractionating the light source to improve oxygenation and the therapeutic response of PDT. (Foster et al., Analysis of Photochemical Oxygen Consumption Effects in Photodynamic therapy in Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques for Photodynamic Therapy, SPIE, 1645:104-114 (1992); Foster et al., Oxygen Consumption and Diffusion Effects in Photodynamic Therapy, Radiation Research, 126: 296-303 (1991); Foster and Gao, Dosimetry in Photodynamic Therapy: Oxygen and the Critical Importance of Capillary Density, Radiation Research, 130: 379-383 (1992); and Gibson et al., Effects of Various Photoradiation Regimens on the Antitumor Efficacy of Photodynamic Therapy for R3230AC Mammary Carcinomas, Cancer Research, 50: 7236-7241 (1990)). The general improvements achieved by fractionating of the light source have been considered from an experimental standpoint.
One of the factors which increases the cost of photodynamic therapy treatment is the clinical time needed for operating a laser system for treating a cancerous tumor. Doctors, radiologists, and technical staff must carefully operate a complex laser system to concentrate the laser beam on the tumor. Cancer clinics have a need for a system to improve the efficiency of the photodynamic therapy by decreasing the time needed for laser treatment.
Laser systems have been used in various surgical procedures for a number of years. Inoue et al. (U.S. Pat. No. 4,630,273) shows a laser system with a programmable memory system for storing a variety of irradiating modes.
Barken (U.S. Pat. No. 4,672,963) teaches a system and method for computer controlled laser surgery. An ultrasonic probe is used to monitor the condition of the tissue and the position of the laser irradiating device. The computer system provides image reconstruction and monitors the systems parameters such as laser power. The computer controls the laser power and on/off cycle times.
The device for the selective destruction of cells disclosed by Kratzer et al. (U.S. Pat. No. 5,035,693) includes an X-Y optical scanning device. The process involves an initial low power illumination step, a response from the cells, detection by a control means, and a transmission of a high power radiation signal to kill the cells. The goal of such a system, is to provide accurate treatment of a large number of cells.
Danon (U.S. Pat. No. 5,049,147) teaches an apparatus for displaying in real time a visually sensible image of the area of surgery and an overlap of a simulation of the effects of operator indicated laser surgical procedures. Once the laser system is properly positioned and aligned, the high energy is fired to carry out the indicated laser surgical procedure from the display.